Role of lipoxygenase metabolites in platelet-activating factor- and antigen-induced bronchial hyperresponsiveness and eosinophil infiltration

Abstract

The effect of a novel leukotriene B4 receptor antagonist N-[5-[[8-(1-hydroxy-2-phenyl)ethyl]dibenzofuran-2-yl]-5-hydroxypentanoyl] pyrrolidine (PF 10042) has been evaluated in comparison with 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline hydrochloride (PF 5901), a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism, against platelet activating factor (PAF) and allergen induced bronchial hyperresponsiveness and pulmonary eosinophil infiltration in the guinea pig. PF 10042 significantly displaced radiolabelled [3H]leukotriene B4 from binding sites on human neutrophils with an EC50 of 3 μM. PF 10042 (100 mg/kg, i.p.) significantly inhibited PAF and allergen induced bronchial hyperresponsiveness without reducing the concomitant eosinophil infiltration, whereas PF 5901 (100 mg/kg, p.o.) significantly inhibited both PAF and allergen induced bronchial hyperresponsiveness and eosinophil infiltration. We suggest from these results that PAF and allergen induced bronchial hyperresponsiveness may be secondary to the release of leukotriene B4, but this lipoxygenase metabolite does not contribute significantly to the observed eosinophil infiltration.